Xevinapant + RT for High-Risk Cisplatin-Ineligible LA SCCHN

For patients with resected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) at high risk of recurrence and eligible for cisplatin, the standard treatment involves chemoradiotherapy (CRT) combining cisplatin and radiotherapy (RT). However, for those ineligible for cisplatin, treatment options are limited, needing more specific recommendations in international guidelines.

Xevinapant, a novel small-molecule inhibitor of apoptosis protein, has demonstrated the ability to restore cancer cell sensitivity to apoptosis, potentially enhancing the efficacy of chemotherapy and RT.

In a phase 2 randomized trial involving patients with unresected LA SCCHN, the addition of xevinapant to CRT resulted in a 53% reduction in the risk of death after 5 years of follow-up and a 67% lower risk of death or disease progression after 3 years compared to placebo plus CRT. Furthermore, preclinical studies in SCCHN models have shown that xevinapant combined with RT alone exhibits anti-tumor activity.

These promising clinical and preclinical data provide a strong rationale for combining xevinapant + RT in cisplatin-ineligible pts with LA SCCHN.

Robert L. Ferris and the team conducted a study that aimed to investigate the efficacy of combining xevinapant with radiotherapy in cisplatin-ineligible patients with resected, LA SCCHN.

The XRay Vision study is a phase 3 trial, employing a randomized, double-blind, placebo-controlled design. It aims to compare the efficacy of xevinapant or placebo in combination with intensity-modulated radiotherapy (IMRT) in patients (pts) with resected LA SCCHN who are ineligible for cisplatin and have a high risk of relapse.

Eligible patients must have histologically confirmed cancer in specified regions (oral cavity, oropharynx, hypopharynx, or larynx), undergone curative surgery 4–10 weeks before treatment initiation (ideally within 8 weeks), exhibit no residual disease by CT scan, and meet cisplatin ineligibility criteria (meeting ≥1 of the following criteria: eGFR <60 mL/min/1.73 m2; grade ≥2 audiometric hearing loss or grade ≥2 tinnitus; grade ≥2 peripheral neuropathy; and if aged ≥70 years old, unfit according to the G8 questionnaire [score ≤14] or ineligible for cisplatin due to age limit according to national guidelines).

Additional eligibility criteria include an ECOG PS of 0–2 and adequate hematologic and hepatic function. The study aims to randomize approximately 700 eligible pts to receive oral xevinapant (200 mg/day; Days 1–14 of a 3-week cycle) or placebo for 3 cycles, alongside standard fractionation IMRT (66 Gy in 33 fractions, 2 Gy/fraction, 5 days/week), followed by 3 cycles of xevinapant or placebo.

Disease-free survival (DFS) is the primary endpoint; overall survival (OS), time to subsequent cancer treatments, safety, and quality of life (QoL) related to health are the secondary endpoints. Patient follow-up will extend until the completion of assessments for the last patient at 60 months post-randomization or until premature treatment discontinuation.

Follow-up will continue until the assessment of the last patient at 60 months post-randomization or until premature treatment discontinuation. Enrollment is ongoing across 21 countries globally, including the US, Mexico, South America, Europe, and Asia. The study commenced in October 2022, with recruitment ongoing, and results will be presented upon completion.

The trial was sponsored by EMD Serono Research & Development Institute, Inc.

Source: https://astro.confex.com/astro/hncs2024/meetingapp.cgi/Paper/59594

Clinical Trial: https://clinicaltrials.gov/study/NCT05386550 

Ferris RL, Mehanna H, Schoenfeld JD, et al. (2024) ‘’ XRay Vision: a phase 3 study of xevinapant plus radiotherapy (RT) for high-risk, cisplatin-ineligible patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Presented at MHNCS 2024, (107).